Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study.

BACKGROUND: The relative roles of immunodeficiency, HIV viral load, and combination antiretroviral therapy (cART) in the onset of individual cancers have rarely been examined. We examined the effect of these factors on the risk of specific cancers in patients infected with HIV-1. METHODS: We investigated the incidence of both AIDS-defining cancers (Kaposi's sarcoma, non-Hodgkin lymphoma, and cervical cancer) and non-AIDS-defining cancers (Hodgkin's lymphoma, lung cancer, liver cancer, and anal cancer) in 52 278 patients followed up in the French Hospital Database on HIV cohort during 1998-2006 (median follow-up 4.9 years, IQR 2.1-7.9; 255 353 person-years). We tested 78 models with different classifications of immunodeficiency, viral load, and cART with Poisson regression. FINDINGS: Current CD4 cell count was the most predictive risk factor for all malignancies apart from anal cancer. Compared with patients with CD4 count greater than 500 cells per microL, rate ratios (RR) ranged from 1.9 (95% CI 1.3-2.7) for CD4 counts 350-499 cells per microL to 25.2 (17.1-37.0) for counts less than 50 cells per microL for Kaposi's sarcoma (p<0.0001), from 1.3 (0.9-2.0) to 14.8 (9.7-22.6) for non-Hodgkin lymphoma (p<0.0001), from 1.2 (0.7-2.2) to 5.4 (2.4-12.1) for Hodgkin's lymphoma (p<0.0001), from 2.2 (1.3-3.6) to 8.5 (4.3-16.7) for lung cancer (p<0.0001), and from 2.0 (0.9-4.5) to 7.6 (2.7-20.8) for liver cancer (p<0.0001). For cervical cancer, we noted a strong effect of current CD4 (RR 0.7 per log(2), 95% CI 0.6-0.8; p=0.0002). The risk of Kaposi's sarcoma and non-Hodgkin lymphoma increased for current plasma HIV RNA greater than 100 000 copies per mL compared with patients with controlled viral load (RR 3.1, 95% CI 2.3-4.2, p<0.0001; and 2.9, 2.1-3.9, p<0.0001, respectively), whereas cART was independently associated with a decreased incidence (0.3, 0.2-0.4, p<0.0001; and 0.8, 0.6-1.0, p=0.07, respectively). The RR of cervical cancer for those receiving cART was 0.5 (0.3-0.9; p=0.03). The risk of anal cancer increased with the time during which the CD4 count was less than 200 cells per microL (1.3 per year, 1.2-1.5; p=0.0001), and viral load was greater than 100 000 copies per mL (1.2 per year, 1.1-1.4, p=0.005). INTERPRETATION: cART would be most beneficial if it restores or maintains CD4 count above 500 cells per microL, thereby indicating an earlier diagnosis of HIV infection and an earlier treatment initiation. Cancer-specific screening programmes need to be assessed in patients with HIV. FUNDING: Agence Nationale de Recherches sur le SIDA et les hépatites (ANRS), INSERM, and the French Ministry of Health.

Incidence of non-AIDS-defining cancers before and during the highly active antiretroviral therapy era in a cohort of human immunodeficiency virus-infected patients.

PURPOSE: To determine incidence of non-AIDS-defining cancers (NADC) in HIV-infected patients before (P1) and during (P2) the use of highly active antiretroviral therapy (HAART) relative to that observed in the French general population (FGP) of the same age and sex. PATIENTS AND METHODS: Sex- and age-adjusted NADC standardized incidence ratios (SIR), with FGP as reference, were estimated in 1992 to 1995 (P1) and in 1996 to 1999 (P2) in a French Hospital Database on HIV prospective hospital cohort study. RESULTS: NADCs were diagnosed in 260 patients during P1 and 391 patients during P2 among the 77,025 patients included in the database between January 1, 1992, and December 31, 1999. Estimated incidence of all cancers was higher in HIV-infected men than in FGP during both periods (P1 SIR = 2.36 and P2 SIR = 1.91). No excess of cancers was observed among HIV-infected women in either period. Incidence of all cancers did not change from P1 to P2 in either sex (SIR = 0.96 for men and 1.00 for women). In contrast, incidence of Hodgkin's disease (HD) was higher than in FGP in both sexes and both periods and increased in P2 as compared with P1; incidence of lung cancer was higher in both sexes during P2. CONCLUSION: Relative to FGP, the overall incidence of NADCs was increased in HIV-infected men but not in women and did not differ between P1 and P2. Only HD was much more common in HIV infection, and the potential role of HAART on HD cannot be excluded.

Immunologic and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV.

OBJECTIVE: To study immunologic and clinical responses to HAART in patients over 50 years old. DESIGN AND METHODS: A prospective cohort study which included 68 hospitals in France. A total of 3015 antiretroviral-naive patients, 401 of whom were aged 50 years or over, were enrolled following initiation of HAART. The influence of age on the mean CD4 cell count increase on HAART was studied by using a two-slope mixed model. Progression, defined by the occurrence of a new AIDS-defining event (ADE) or death, was studied by Cox multivariate analyses. RESULTS: Among patients with baseline HIV RNA above 5 log copies/ml, CD4 mean increase during the first 6 months on HAART was +42.9 x 10(6) cells/l per month in patients under 50 years and +36.9 x 10(6) cells/l per month in patients over 50 years (P < 0.0001); subsequently, the respective monthly changes were +17.9 and +15.6 x 10(6) cells/l per month (P < 0.0001). Similar trends were observed in patients with baseline HIV RNA below 5 log copies/ml, and also after stratification for the baseline CD4 cell count. After a median follow-up of 31.5 months, 263 patients had a new ADE and 44 patients died. After adjustment for baseline characteristics, older patients had a significantly higher risk of clinical progression (hazard ratio (HR) = 1.52 [95% confidence interval (CI), 1.15-2.00]) and were more likely to achieve a viral load below 500 copies/ml [HR = 1.23, (95% CI, 1.11-1.38)]. CONCLUSION: Patients over 50 years of age have an immunologic response to HAART. However, their CD4 cell reconstitution is significantly slower than in younger patients, despite a better virologic response. This impaired immunologic response may explain their higher risk of clinical progression.

Role of long-term nucleoside-analogue therapy in lipodystrophy and metabolic disorders in human immunodeficiency virus-infected patients.

The role of nucleoside analogues (NAs) in lipodystrophy (LD) syndrome in human immunodeficiency virus (HIV)-infected patients remains controversial. We studied the prevalence of LD in previously untreated patients randomized to receive different NA combinations (in the ALBI-ANRS 070 trial) for 6 months. At month 30 of follow-up, 37 (31%) of 120 patients had >/=1 morphologic change, and 21 (57%) of 37 had isolated peripheral lipoatrophy; corresponding values for the patients who received only NAs throughout follow-up were 20 (30%) of 66 and 14 (67%) of 21, respectively. In multivariate analysis, factors associated with presence of LD at month 30 were initial assignment to the group receiving stavudine and didanosine (odds ratio [OR], 6.7; P=.02), age (OR for being 10 years older, 3.6; P=.002), and HIV RNA level at month 30 (OR, 0.4; P=.007). No difference was observed in cholesterol and glucose levels as a function of any pattern of antiretroviral exposure. Exposure to stavudine and didanosine was associated with LD syndrome (predominantly lipoatrophy).

Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus: Inverse Gaussian density absorption and 2-compartment disposition.

OBJECTIVE: Enfuvirtide (T-20) is the first of a novel class of human immunodeficiency virus (HIV) drugs that block gp41-mediated viral fusion to host cells. The objectives of this study were to develop a structural pharmacokinetic model that would adequately characterize the absorption and disposition of enfuvirtide pharmacokinetics after both intravenous and subcutaneous administration and to evaluate the dose proportionality of enfuvirtide pharmacokinetic parameters at a subcutaneous dose higher than that currently used in phase III studies. METHODS: Twelve patients with HIV infection received 4 single doses of enfuvirtide separated by a 1-week washout period in an open-label, randomized, 4-way crossover fashion. The doses studied were 90 mg (intravenous) and 45 mg, 90 mg, and 180 mg (subcutaneous). Serial blood samples were collected up to 48 hours after each dose. Plasma enfuvirtide concentrations were measured with use of a validated liquid chromatography-tandem mass spectrometry method. RESULTS: Enfuvirtide plasma concentration-time data after subcutaneous administration were well described by an inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment. The model-derived mean pharmacokinetic parameters (+/-SD) were volume of distribution of the central compartment (3.8 +/- 0.8 L), volume of distribution of the peripheral compartment (1.7 +/- 0.6 L), total clearance (1.44 +/- 0.30 L/h), intercompartmental distribution (2.3 +/- 1.1 L/h), bioavailability (89% +/- 11%), and mean absorption time (7.26 hours, 8.65 hours, and 9.79 hours for the 45-mg, 90-mg, and 180-mg dose groups, respectively). The terminal half-life increased from 3.46 to 4.35 hours for the subcutaneous dose range from 45 to 180 mg. CONCLUSIONS: An inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment was appropriate to describe complex absorption and disposition kinetics of enfuvirtide plasma concentration-time data after subcutaneous administration to patients with HIV infection. Enfuvirtide was nearly completely absorbed from subcutaneous depot, and pharmacokinetic parameters were linear up to a dose of 180 mg in this study.

An example of nonrandom missing data for hepatitis C virus status in a prognostic study among HIV-infected patients.

PURPOSE: To describe information bias due to missing data for hepatitis C (HCV) status in the analysis of factors associated with mortality in HIV-infected patients. METHOD: The prospective APROCO cohort enrolled 1,151 HIV-infected adults at the first initiation of highly active antiretroviral treatment in 1997-1998. Conversely to other characteristics, hepatitis B and C serologic status were recorded retrospectively. RESULTS: In a first dataset, HCV status was missing in 29%. HCV infection was associated with a higher hazard of death (Cox model, hazard ratio [HR]=4.1; 95% confidence interval [95% CI], 1.5-11.3). After more efforts to actively document HCV status, the information remained missing in only 10%. All deceased patients who were secondarily documented were recorded as being HCV negative. In fact, before systematic collection of HCV status, nonstructured additional documentation for all deaths led to spontaneous notification of HCV-positive serology at death and not HCV negative. HCV was no longer associated with the hazard of death (HR=1.2; 95% CI, 0.6-2.7). CONCLUSION: These results underline the need to minimize missing data and to investigate the impact of missing data on the results, although the mechanism of bias is difficult to identify. In addition, these results might shed light on the current debate about the association between HCV and progression of HIV infection.

The cost of managing HIV infection in highly treatment-experienced, HIV-infected adults in France.

BACKGROUND: Highly active antiretroviral therapy (HAART) has greatly enhanced HIV management, lowering the risk of clinical disease progression and death by substantially improving HIV-induced immune deficiency. Lower CD4 cell counts have consistently been associated with higher direct costs of HIV patient care. The aim of this study was to analyze HIV costs of care in France at different levels of HIV-induced immune deficiency (as measured by the CD4 cell count) using recent data from treatment-experienced patients. METHODS: This analysis used data from the French Hospital Database in HIV, containing data on approximately 50% of the French HIV population. Patients were included in the analysis if they had visited a participating centre from 2003 to 2005, had CD4 cell counts determined at least twice during the study period, and had been prescribed at least two nucleoside reverse transcriptase inhibitors, one non-nucleoside reverse transcriptase inhibitor and two protease inhibitors since their first consultation. Resources consumed were counted and aggregated according to the CD4 cell count level. Standard costs were applied. RESULTS: Periods with the lowest CD4 cell counts were associated with increased prescription rates of antiviral agents (other than anti-HIV agents), antiparasitic drugs and antimycobacterial agents. Antiretroviral treatments accounted for 80% of all medications prescribed during the study period. Hospitalization rates decreased with increasing CD4 cell counts, with 0.72 hospitalizations per patient-year for those with CD4 cell counts of 50 cells/mm³ or less compared with 0.05 per patient-year for patients with CD4 cell counts greater than 500 cells/mm³. There was a clear trend towards lower mean healthcare costs per patient-year with decreasing immune deficiency; from €34,286 to €12,361. CONCLUSIONS: Our study showed an association between the degree of HIV-induced immune deficiency (measured by CD4 cell count) and the costs of managing HIV infection among highly pre-treated, HIV-infected individuals in France in the HAART era.

Occult hepatitis B in HIV-HCV coinfected patients.

The prevalence of occult hepatitis B infection in HIV infected patients is controversial, varying from less than 1% to 62% in different studies. Blood samples of 111 HIV-infected patients, HCV-positive, HBs antigen negative, followed in the APROCO-ANRS EP11 cohort, were used to detect HBV DNA by using 2 different validated assays (Cobas Amplicor HBV Monitor Test and INSERM U271 qualitative ultra-sensitive PCR), completed when positive by HBV real-time PCR. HBV DNA was found in 6 (5.4%, 95% CI 1.2%-9.6%) patients by at least 1 of these assays, but none tested positive in all 3 assays. All 6 patients had anti-HBc without anti-HBs antibodies; 5 were not on lamivudine. Their median CD4 and CD8 counts were significantly lower and their HIV viral load higher than in the other 105 patients. In conclusion, the prevalence of occult hepatitis B may vary significantly according to the molecular assay used, even though these assays are validated with high specificity and quite high sensitivity. Occult hepatitis B may be encountered in HIV-HCV coinfected patients without anti-HBV treatment, with anti-HBc but without anti-HBs antibodies, and relatively low immunity, suggesting a potential risk of further reactivation, as already sporadically reported.

Self-reported side-effects of anti-retroviral treatment among IDUs: a 7-year longitudinal study (APROCO-COPILOTE COHORT ANRS CO-8).

The introduction of potent anti-retroviral treatment (ART) has transformed HIV disease into a chronic condition with the prospect, for the patient, of strict adherence to effective but life-long treatments. Within this framework, a major issue that can negatively affect adherence is the side-effects of the treatment. To date, studies documenting how individuals HIV-infected through drug injection (IDUs) experience ART-related side effects are sparse. Longitudinal data collected from the APROCO-COPILOTE cohort have been used to compare the experience of ART-related side-effects who have been HIV-infected via injecting drug use and non-IDU patients. A 20-item list was used to collect self-reported side-effects over a 7-year follow up period. Of 922 patients, 15% were IDUs. At any given visit, IDUs reported a significantly higher number of side-effects and had approximately twice the risk of reporting any side effect than non-IDUs. Most commonly reported side-effects were dry skin, fatigue, vomiting, bone troubles, insomnia. After adjustment for social conditions, depressive symptoms, use of sleeping pills and time since HIV diagnosis, IDUs reported experiencing significantly more side-effects than non-IDUs. Whether or not this is related to sensitivity to pain or to other comorbidities is difficult to establish. Further research is needed to understand how substitution treatment can mediate the relationship between exposure to opioids and side-effects. Providing appropriate care to reduce side-effects, thereby increasing adherence to ART in this population, remains a major challenge especially in those countries scaling up ART. Incorporating symptom management and improving access to analgesic medications within a model of comprehensive care for HIV-infected IDUs, could reduce the impact of drug-related and HIV-related harms and induce better long-term treatment outcomes and quality of life.

Virologic response of zidovudine, lamivudine, and tenofovir disoproxil fumarate combination in antiretroviral-naive HIV-1-infected patients.

BACKGROUND: High rates of virologic failure have been reported in antiretroviral-naive patients receiving triple-nucleoside reverse transcriptase inhibitor (NRTI) combinations containing tenofovir disoproxil fumarate (TDF) with lamivudine (3TC) and didanosine or 3TC and abacavir (ABC). A regimen of once-daily zidovudine (ZDV), 3TC, ABC, and TDF showed an acceptable virologic success rate, however. METHODS: This was a pilot prospective cohort study. Treatment-naive subjects were offered a fixed-dose combination of ZDV/3TC (300 mg/150 mg) twice daily and 300 mg of TDF once daily. RESULTS: Fifty-one patients were enrolled between April 2002 and March 2005. At baseline, the median CD4 count was 230 cells/microL (range: 23-425 cells/microL), 20 (39%) of 51 subjects had CD4 counts of < 200 cells/microL, the median HIV-1 viral load was 4.89 log (3.14 to >5.87 log), and 24 (47%) of 51 subjects had a viral load >5 log. The median follow-up was 12 months (range: 1 week to 38 months). On-treatment analysis showed a median HIV RNA load decrease of -1.7 log after 1 to 2 weeks of treatment and -2.41 log after 1 month, and 34 (89%) of 38 subjects had a viral load < 50 copies/mL at month 6, 21 (78%) of 27 at month 12, and 13 (81%) of 16 after 18 months (intent-to-treat results were 34 [72%] of 47 subjects, 21 [56%] of 36 subjects, and 13 [50%] of 25 subjects at months 6, 12, and 18, respectively). The median CD4 count increase at month 18 was 142 cells/microL. Nine (17.6%) of 51 treatment interruptions for adverse effects were seen. Six viral failures occurred, including 2 with K65R mutations (alone or associated with Y115F and M184V). CONCLUSION: The combination of ZDV/3TC + TDF in treatment-naive HIV-infected subjects induces a rapid and sustained HIV-1 RNA decrease and is associated with a good immunologic response. No severe adverse events occurred. This triple-NRTI combination needs to be evaluated further.

Encouraging results despite complexity of multidisciplinary care of HIV-infected women using assisted reproduction techniques.

BACKGROUND: Assisted reproduction technologies can treat infertility for human immunodeficiency virus (HIV) seropositive women. We assessed the efficacy of these techniques in the results and difficulties encountered while conducting our assisted reproduction programme for 49 couples in which at least the woman had HIV infection that was currently under control. METHODS: Treatments included intrauterine insemination (IUI), IVF and ICSI, with ovarian stimulation. Embryos were transferred on day 3 after oocyte retrieval. An elective single transfer was performed, except for patients aged > or = 40 years. RESULTS: The median age of the women was 36 years. Ten IUI, nine IVF, 53 ICSI and 10 frozen-thawed embryo transfers have been performed. No pregnancy occurred following the IUI trials but for the couples with IVF and ICSI attempts the clinical pregnancy rate per embryo transfer was 23.9%. Eight babies have been born leading to a 22.2% take home baby rate per treated couple. Contamination was not observed in any newborn. CONCLUSIONS: Assisted reproduction technologies and particularly ICSI can provide HIV seropositive women with a safe means of mothering children. Results are encouraging when considering the age of the patients and a preferential single embryo transfer.

Tolerance of a short course of nevirapine, associated with 2 nucleoside analogues, in postexposure prophylaxis of HIV.

A combination of 2 nucleoside analogues and 1 protease inhibitor is usually recommended in postexposure prophylaxis. Because of the complex treatment schedule and frequent adverse effects, however, this regimen is often not completed. Therefore, since January 2000, we have used nevirapine (NVP), 200 mg/d, for only 4 days in combination with 2 nucleoside analogues for 1 month to improve adherence and completion rates. We present a 2-year retrospective analysis on 120 individuals who received this prophylaxis. Only 2 subjects stopped NVP because of a clinical event, whereas 10 interrupted the nucleoside analogues. We observed 3 (2.8%) of 104 slight alanine aminotransferase (ALT) increases in the first 2 weeks of treatment (grade 1). Three additional (month 1 or 3) ALT augmentations also occurred (also grade 1). No HIV or hepatitis C virus seroconversion occurred during follow-up. Twenty-nine (38.2%) of 76 individuals and 21 (47.7%) of 44 individuals were seen 3 months after nonoccupational and occupational exposure, respectively. We believe that such a short course (4 days) of 200-mg NVP treatment once a day in combination with 2 nucleoside analogues for 1 month is clinically and biologically safe.

Assisted reproduction techniques for HIV serodiscordant couples: 18 months of experience.

BACKGROUND: Assisted reproduction techniques can minimize the risk of infection and treat possible sterility associated with serodiscordant couples. METHODS: We assessed the efficacy of these techniques in 57 couples in which at least one partner had human immunodeficiency virus (HIV-1) infection that was currently under control (47 men and 10 women). The semen of seropositive men was prepared and tested for viruses. Assisted reproduction techniques included intrauterine insemination (IUI), IVF and especially ICSI, with ovarian stimulation that used a long agonist protocol and recombinant FSH. Embryos were transferred on day 3 after oocyte retrieval. RESULTS: For couples with seropositive men, five IUI and 49 IVF or ICSI attempts were perfomed, whilst for seropositive women these numbers were three IUI and 12 IVF or ICSI. No pregnancy occurred following the eight IUI trials. Seroconversion was not observed in any partners of seropositive men. Efficacy of treatment for these couples with ICSI was good, the clinical pregnancy rate per embryo transfer was 48.8%. The results for seropositive women were disappointing, with a clinical pregnancy rate per embryo transfer of 9.1%. Fourteen babies from 47 treated couples have so far been born and no pregnancies from IUI. CONCLUSIONS: Assisted reproduction techniques and particularly ICSI provide HIV-1-seropositive men with a safe and highly effective means of fathering children. These techniques may be less effective for seropositive women.

Health-related quality of life after 1 year of highly active antiretroviral therapy.

OBJECTIVE: We investigated the impact of the first year of highly active antiretroviral therapy (HAART) on health-related quality of life (HRQL). METHODS: Medical data for patients in the French APROCO cohort were collected at enrollment (M0) and month 12 (M12). A self-administered questionnaire gathered information about HRQL (Medical Outcome Study 36-Item Short Form Health Survey) and toxicity-related symptoms. Using the twenty-fifth percentile of HRQL scales in the French population as a threshold, patients with normal values in at least three mental and three physical scales were considered to have a "normal HRQL." RESULTS. Of the 1053 patients followed through M12, HRQL data at M0 and M12 were available for 654. Among the 233 patients with a normal baseline HRQL, 63 (27.0%) experienced a deterioration of HRQL at M12. Among the 421 patients with a low baseline HRQL, 121 achieved a normal HRQL at M12. Logistic regression showed that factors independently associated with a normal HRQL at M12 were normal baseline HRQL, baseline CD4 count <500 cells/mm, time since HIV diagnosis <8 years, undetectable HIV-RNA at M12, and lower number of self-reported symptoms at M12. CONCLUSION: An assessment of HRQL should be integrated to efficacy outcomes to evaluate and compare long-term strategies properly and to optimize the durability of response to antiretroviral therapy.