Jeanette Vizzard

Transmission of Human Immunodeficiency Virus Type 1 Resistant to Nevirapine and Zidovudine

Human immunodeficiency virus type 1 (HIV-1) resistant to the nonnucleoside reverse transcriptase inhibitor nevirapine and to the nucleoside analogue zidovudine was transmitted from a homosexual man to his sex partner. The virus source patient had commenced combination zidovudine and nevirapine therapy 2.5 years prior to his partners primary HIV infection. He received both therapies for 7 months, then discontinued nevirapine treatment, continuing to receive zidovudine monotherapy for a further 16 months. He had ceased zidovudine therapy 6 months before the time of his partners seroconversion. Analysis of major and minor isolates obtained from both patients soon after onset of the recipients primary HIV infection illness confirmed that an HIV-1 variant mutant at codons 70, 98, and 181 of the viral reverse transcriptase was transmitted. This is the first documented case of transmission of HIV-1 resistant to two antiretroviral compounds.

Potent Antiretroviral Therapy of Primary Human Immunodeficiency Virus type 1 (HIV-1) Infection: Partial Normalization of T Lymphocyte Subsets and Limited Reduction of HIV-1 DNA Despite Clearance of Plasma Viremia

Antiretroviral therapy commenced during primary human immunodeficiency virus type 1 (HIV-1) infection (PHI) may limit the extent of viral replication and prevent early loss of HIV-specific CD4 lymphocyte function. We studied the effect of current standard therapy (2 nucleoside analogues and a protease inhibitor) in 16 patients with symptomatic PHI. In the 13 patients who completed 1 year of treatment, plasma HIV RNA was <50 copies/mL and median CD4 cell counts were comparable to HIV-uninfected controls, with naive (CD45RA+CD62L+), primed (CD45RO+), and T cell receptor Vbeta subsets all within normal ranges. However, HIV-1 DNA levels in treated and untreated PHI patients were similar. Furthermore, CD8 cell counts remained elevated, including activated (CD38+HLA-DR+), replicating (Ki-67+), and cytotoxic (perforin+CD28-) lymphocytes. In conclusion, early antiretroviral therapy resulted in clearance of viremia and prevented loss of crucial CD4 subsets. The persistence of HIV-1 DNA together with increased CD8 T lymphocyte turnover and activation indicate continued expression of viral antigens.

Patterns of Viral Dynamics during Primary Human Immunodeficiency Virus Type 1 Infection

This study used curve-fitting techniques to detail the dynamics of human immunodeficiency virus (HIV)-1 and its relationship to circulating T lymphocyte changes in a cohort of 41 male patients (mean age 36+/-7 years) infected with HIV-1. The following characteristics of viral kinetics were obtained: virus load peak, 6. 35+/-0.71 log10 RNA copies/mL at 12.2+/-7.1 days; virus load drop from peak, 2.02+/-0.93 log10 copies/mL; viral decay rate from peak, 0.071+/-0.042 log10 RNA copies/mL/day; and steady state virus load, 4.57+/-0.68 log10 copies/mL at 135+/-81 days. Analysis of individual virus load curves revealed highly variable viral kinetics. Although these could be grouped into three distinct patterns, virus load and CD4 lymphocyte counts were similar in all patterns at 12 months, but the interval from infection to achievement of steady state virus load varied significantly.

Severity and Prognosis of Acute Human Immunodeficiency Virus Type 1 Illness: A Dose-Response Relationship

This study examined the relationship between the severity of acute human immunodeficiency virus type 1 (HIV-1) illness and disease progression and death. The population included 218 patients with acute HIV-1 illness and 41 asymptomatic patients who underwent HIV-1 seroconversion; the patients were followed up prospectively. We analyzed progression to Centers for Disease Control and Prevention clinical categories B and C (AIDS-defining conditions) and death according to an additive clinical score (CS) based on six predictive clinical features at the time of acute HIV-1 infection. Compared with patients with a CS of 0 (asymptomatic patients), those with a CS of 3-4 and 5-6 had faster progression to category B disease (adjusted hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.01-1.92; and HR, 1.80; 95% CI, 1.34-2.40; respectively); those with a CS of 5-6 had faster progression to category C disease (HR, 1.37; 95% CI, 1.01-1.89) and death (HR, 2.05; 95% CI, 1.27-3.32). Thus, the number of symptoms and signs at the time of acute HIV-1 illness affects disease progression and survival, even in symptomatic patients who have undergone seroconversion.

Incubation time of acute human immunodeficiency virus (HIV) infection and duration of acute HIV infection are independent prognostic factors of progression to AIDS

The severity and the duration of acute human immunodeficiency virus (HIV) infection (AHI) are associated with a faster rate of progression to AIDS, but the prognostic value of the length of incubation time of AHI (IncAHI), defined as the time between HIV infection and AHI, on progression to AIDS has not been assessed. We explored this issue prospectively in 70 individuals with documented AHI and a known date of HIV infection. The median IncAHI was 21.5 days (range, 5-70 days), and the median duration of AHI was 15.5 days (range, 3-67 days). The adjusted relative hazard of progression to AIDS or to a CD4(+) count <200x103/mL was 4.23 (95% confidence interval [CI], 1.40-12.73; P=.01) for the patients with an IncAHI <21.5 days, compared with those with longer IncAHI, and was 3.53 (95% CI, 1.09-11.36; P=.03) for the patients with a duration of AHI >15.5 days, compared with those with shorter duration. Both IncAHI and duration of AHI were independent predictors of progression. This suggests that early pathogenic events before the onset of AHI influence the rate of HIV disease progression.

Clinical features of acute retroviral syndrome differ by route of infection but not by gender and age

The rate of HIV disease progression is associated with the severity of the acute retroviral syndrome (ARS). We explored the clinical features of ARS by gender, age and route of infection among 378 individuals with documented ARS enrolled in 5 prospective cohort studies with similar enrollment criteria. No major differences were detected by gender or by age. Several symptoms were reported less frequently in the injecting drug users as compared with infection acquired through sexual contacts (either heterosexual or homosexual). This was observed in particular for fever (50% vs. 77%, p=.001), skin rash (21% vs. 51%, p=.001), pharyngitis (18% vs. 43%, p=.004), and myalgia (29% vs. 52%, p=.01). Genital ulcerations were present only in cases of sexual exposure to HIV. Injecting drug users had or reported symptoms associated with the ARS less frequently than persons acquiring HIV via sexual transmission.

Comparison of clinical features, CD4 and CD8 responses among patients with acute HIV-1 infection from Geneva, Seattle and Sydney.

ObjectiveTo compare the clinical features and T-cell subsets among 160 patients with acute HIV-1 infection not treated with antiretroviral agents from three different locations (Geneva, Seattle and Sydney). DesignPatients with documented acute HIV-1 infection were enrolled in four prospective studies: one randomized placebo controlled trial (RCT) and three observational cohort studies. SettingAll patients were diagnosed and followed in three university affiliated tertiary clinical care centers. MethodsThe chi-square test was used for comparing proportions and one way analysis of variance (ANOVA) for comparing continuous variables among these groups. Multiple regression analysis was used to identify the variables independently associated with the duration of acute HIV-1 infection. The differences in mean CD4 and CD8 load between centers were assessed using the random-effect models for the longitudinal data. ResultsMinor differences were noted in the frequency of symptoms among subjects enrolled at different locations. RCT patients reported a longer duration of symptoms (31 days) compared with that for observational patients (15 days;P < 0.0001). For the most common symptoms such as fever, skin rash, arthralgia, myalgia, and headaches, a longer duration was observed in the RCT group compared with that for observational patients (P range, 0.001 to < 0.0001). T-cells subsets within 100 days of seroconversion did not statistically differ by centre or by mode of recruitment. ConclusionsThese results suggest a selection bias toward patients with longer symptomatic acute HIV-1 infection enrolled in the RCT. Data collected from RCT are not comparable to that collected in observational studies. However, data from collaborative international studies can be combined.

Long-term prognosis following zidovudine monotherapy in primary human immunodeficiency virus type 1 infection.

Eighty-five subjects with symptomatic primary (P) human immunodeficiency virus (HIV) type 1 infection were analyzed in a retrospective cohort study to investigate the long-term clinical benefit of antiretroviral treatment during PHIV infection. Zidovudine treatment was initiated (PHIV treatment group) in 21 persons a median of 9 days after onset of PHIV symptoms and continued for a median of 55 days (range, 21-99). Sixty-four subjects did not receive early antiretroviral treatment (PHIV nontreatment group). After follow-up for 3-10 years, 33 subjects had developed AIDS and 22 subjects had died of AIDS. The median times for progression to AIDS and death were 6.4 and 9.1 years, respectively. Progression rates did not differ between the PHIV treatment and nontreatment groups. Zidovudine treatment initiated during PHIV infection did not improve long-term outcome after symptomatic PHIV infection.

Incubation and duration of specific symptoms at acute retroviral syndrome as independent predictors of progression to AIDS

The incubation and duration of acute retroviral syndrome (ARS) have been associated with progression to AIDS. We assessed the independent effect of specific symptoms at ARS on the rate of progression to AIDS or a CD4+ count of <200 cells/mm3 in 70 ARS patients. The incubation and duration of ARS features were stratified on their medians. The Cox regression model was used to calculate the adjusted relative hazard (ARH) of progression. Short incubations of fever (ARH = 5.8, P = 0.004), fatigue (ARH = 2.7, P = 0.06), and myalgia (ARH = 3.8, P = 0.04) were associated with faster disease progression, as was the long duration of most symptoms (ARH range: 3.1–8.1, P < 0.03 to P < 0.001). Pathogenetic mechanisms involved in the incubation of ARS features may be associated with progression to AIDS.

Short-term risk of AIDS according to current CD4 cell count and viral load in antiretroviral drug-naive individuals and those treated in the monotherapy era

Background: One key piece of information required when deciding whether to initiate antiretroviral therapy is the risk of AIDS before the next clinic visit. Information on the short-term (6-month) risk of AIDS according to the current viral load and CD4 cell count in untreated individuals and those treated in the zidovudine monotherapy era (i.e., pre-September 1995), especially in those with CD4 cell count > 200 × 106 cells/l, is lacking. Methods: Risk of AIDS was assessed in 3226 subjects with viral load and CD4 cell count known before initiation of antiretroviral therapy or during the zidovudine monotherapy era. These were from CASCADE Collaboration in which data from 20 cohorts of individuals with known dates of seroconversion to HIV, based in clinics in Europe and Australia, have been combined. Results: During a total 5126.0 person-years of follow-up, 219 individuals developed AIDS. In those with current CD4 cell count < 200 × 106 cells/l, 6-month risks were 4.9, 12.7, 17.7 and 22.4% for viral load groups < 10 000, 10 000–29 999, 30 000– 99 999 and ⩾ 100 000 copies/ml, respectively. For CD4 cell counts 200–349 × 106 cells/l risks were 0.5, 1.6, 3.2 and 4.7%, respectively, for the four viral load groups while the corresponding values for group with CD4 cell count ⩾ 350 × 106 cells/l were 0.2%, 0.5%, 0.9% and 2.2%, respectively. Results were similar when analysis was restricted to those with no antiretroviral drug experience. Older people had a higher risk of AIDS for a given CD4 cell count and viral load than younger people. Conclusion: Combined with consideration of other issues, these estimates should prove useful information when deciding whether to initiate antiretroviral therapy in HIV-infected individuals.