Comparison of single and boosted protease inhibitor versus nonnucleoside reverse transcriptase inhibitor-containing cART regimens in antiretroviral-naïve patients starting cART after January 1, 2000.

BACKGROUND: Few published studies have considered both the short- and long-term virologic or immunologic response to combination antiretroviral therapy (cART) and the impact of different cART strategies. PURPOSE: To compare time to initial virologic (<500 copies/mL) or immunologic (>200/mm3 cell increase) response in antiretroviral-naïve patients starting either a single protease inhibitor (PI; n = 183), a ritonavir-boosted PI regimen (n = 197), or a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based cART regimen (n = 447) after January 1, 2000, and the odds of lack of virologic or immunologic response at 3 years after starting cART. METHOD: Cox proportional hazards models and logistic regression. RESULTS: After adjustment, compared to patients taking an NNRTI-regimen, patients taking a single-PI regimen were significantly less likely to achieve a viral load (VL) <500 copies/mL (relative hazard [RH] 0.74, 95% CI 0.54-0.84, p = .0005); there was no difference between the boosted-PI regimen and the NNRTI regimen (p = .72). There were no differences between regimens in the risk of >200/mm3 CD4 cell increase after starting cART (p > .3). At 3 years after starting cART, patients taking a single-PI-based regimen were more likely to not have virologic suppression (<500 copies/mL; odds ratio [OR] 1.60, 95% CI 1.06-2.40, p = .024), while there were no differences in the odds of having an immunologic response (>200/mm3 increase; p > .15). This model was adjusted for CD4 and VL at starting cART, age, prior AIDS diagnosis, year of starting cART, and region of Europe. CONCLUSION: Compared to patients starting an NNRTI-based regimen, patients starting a single-PI regimen were less likely to be virologically suppressed at 3 years after starting cART. These results should be interpreted with caution, because of the potential biases associated with observational studies. Ultimately, clinical outcomes, such as new AIDS diagnoses or deaths, will be the measure of efficacy of cART regimens, which requires the follow-up of a very large number of patients over many years.

Cardio- and cerebrovascular events in HIV-infected persons.

OBJECTIVE: Recent results from the D:A:D Study indicated that the incidence of myocardial infarction (MI) increased by 26% per year of exposure to combination antiretroviral treatment (CART). The present study was performed to investigate whether this risk was similar when including other cardio- and cerebro-vascular disease events (CCVE). DESIGN: D:A:D is an international collaboration of 11 cohorts, following 23 468 HIV-infected patients prospectively at 188 clinics in 21 countries situated in Europe, USA and Australia. METHODS: The end-point was the occurrence of a first CCVE during prospective follow-up, defined as the first of: acute MI, invasive cardiovascular procedures, stroke, or death from other cardiovascular disease. Relative rates (RR) for CCVE from Poisson regression models and 95% confidence intervals (CI) are reported. All models are adjusted for other risk factors for CCVE, including age, gender, ethnicity, family history, body mass index, and smoking status as well as cohort and HIV transmission group. RESULTS: Over 36 145 person-years of follow-up, 207 patients experienced at least one CCVE (23.7% fatal). The first event was MI in 126 patients, invasive cardiovascular procedure in 39 patients, stroke in 38 patients, and death from other cardiovascular disease in four patients. The incidence of first CCVE was 5.7 per 1000 person-years [95% confidence interval (CI) 5.0-6.5] and increased with longer exposure to CART (RR per year of exposure, 1.26; 95% CI, 1.14-1.38; P < 0.0001). CONCLUSION: CART increases the risk of CCVD, and this increase is comparable with how CART affects the risk of MI. This finding is consistent with the hypothesis that atherosclerosis is a side-effect of CART.

Pharmacokinetics of zidovudine in HIV-positive patients with liver disease.

The pharmacokinetics of zidovudine (ZDV) have been studied in eight AIDS patients with normal liver function, and in four AIDS patients with liver disease. Patients who were previously untreated with ZDV were given 250 mg ZDV, and plasma levels of ZDV and its glucuronic metabolite, GZDV, were determined at 0.5, 1, 1.5, 2, 3, and 4 hours after the dose. In patients with liver disease, Cmax and AUC of ZDV were higher, the oral clearance was only one-eighth that of patients without liver disease, and the elimination half-life was longer. There was a trend for concentrations of the principal metabolite, GZDV, to be lower in patients, and, therefore, the ratio of the AUC for GZDV to that for ZDV was much lower in patients with liver disease. Therefore, HIV-seropositive patients with liver disease had the same markedly altered disposition of ZDV as seronegative patients with liver disease. Although this therapy was not clearly associated with a higher incidence of toxicity, some patients with liver disease had to discontinue therapy because of intolerance; therefore, plasma levels of these patients should be monitored when such therapy is undertaken.

HLA-associated susceptibility to HIV-1 infection.

We studied HLA antigen distribution of 50 heterosexual partners of HIV+ drug abusers with more than 1 year of sexual exposure to HIV, 36 children born to seropositive mothers and 61 haemophiliac patients exposed to presumably infectious clotting factor concentrates. B52 and B44 antigens were associated with HIV resistance while B51 was associated with HIV susceptibility. Forty-nine HIV+ drug abusers, spouses of heterosexual partners studied and 25 HIV+ mothers of the children were also typed. DR11 phenotype was associated with infectiousness of HIV+ subjects. Our data suggest that the HLA region controls susceptibility to infection with HIV and infectiousness of HIV+ subjects in different risk groups.

Intrafamilial spread of hepatitis B virus infection. (Role of chronic hepatitis and of the hepatitis B e antigen).

Two hundred and forty household contacts of 85 chronic HBsAg carriers were studied to assess the relationship between liver histology and 'e' antigen or antibody positivity in the index carrier, and evidence of HBV infection within the family. Liver biopsy results were available in 54 index carriers. The prevalence of HBsAg and anti-HBs in the families of 29 carriers with chronic hepatitis and 25 carriers with either a normal liver or minimal inflammatory changes was not significantly different. Serum from 72 index carriers was available for HBeAg and anti-HBe testing. The prevalence of HBsAg and anti-HBs in the families of 5 HBeAg positive carriers, 59 anti-HBs positive subjects, and 8 carriers negative for both HBeAg and anti-HBe was again not significantly different. Infectivity of a carrier thus does not appear to correlate either with histological evidence of liver damage or with the 'e' antigen or antibody positivity of the carrier.

Chronic asymptomatic HBSAg carriers: histologic abnormalities and diagnostic and prognostic value of serologic markers of the HBV.

Liver histology, the serum "e" antigen system, and DNA-polymerase activity were studied in 68 chronic asymptomatic HBSAg carriers with normal liver chemistries in order to assess the frequency of chronic hepatitis and the diagnostic and prognostic usefulness of serum HBV markers in these subjects. Liver histology was normal in 3 cases, showed nonspecific changes in 46, chronic-persistent hepatitis in 16, and moderate chronic active hepatitis in 3. The "e" antigen and DNA-polymerase activity were positive in 2 and 5 cases, respectively, and were associated with either minimal inflammatory changes or chronic-persistent hepatitis. The "e" antibody was found in 28, evenly distributed among the varios histologic categories; 2 out of 3 patients with chronic active hepatitis carried the "e" antibody. Sixty-four patients have been followed prospectively for 12-30 mo with serial liver tests. During follow-up, 1 patient, with minimal inflammatory changes on liver biopsy and negative for "e" antigen, antibody or DNA-polymerase activity, developed consistently abnormal transaminases, and showed progression to chronic active hepatitis on repeat biopsy. In another patient with chronic-persistent hepatitis, "e" antigen and DNA-polymerase activity reverted to entirely normal serologic status. In our large series, the frequency of chronic hepatitis among HBSAg carriers with normal liver chemistries was somewhat higher than previously reported. In these subjects, the "e" antigen status did not correlate closely with liver histology and did not seem to provide reliable short-term prognostic information.