Correlates of psychological intimate partner violence with HIV care outcomes on patients in HIV care.

BACKGROUND: Among people living with HIV (PLWH), physical intimate partner violence (IPV) is associated with poor virologic, psychiatric, and behavioral outcomes. We examined non-physical, psychological intimate partner violence (psy-IPV) and HIV care outcomes using data from two U.S. consortia. METHODS: We conducted multivariable analyses with robust standard errors to compare patients indicating/not indicating psy-IPV. RESULTS: Among PLWH (n = 5950), 9.5% indicated psy-IPV; these individuals were younger (- 3; 95% CI [- 2,-4], p-value < 0.001), less likely to be on antiretroviral treatment (ART) (0.73 [0.55,0.97], p = 0.03), less adherent to ART (- 4.2 [- 5.9,-2.4], p < 0.001), had higher odds of detectable viral load (1.43 [1.15,1.78], p = 0.001) and depression (2.63 [2.18,3.18], p < 0.001), and greater use of methamphetamines/crystal [2.98 (2.30,3.87),p < 0.001], cocaine/crack [1.57 (1.24,1.99),p < 0.001], illicit opioids [1.56 (1.13,2.16),p = 0.007], and marijuana [1.40 (1.15,1.70), p < 0.001]. CONCLUSION: Psychological IPV, even in the absence of physical or sexual IPV, appears to be associated with HIV care outcomes and should be included in IPV measures integrated into routine HIV care.

Anemia risk factors among people living with HIV across the United States in the current treatment era: a clinical cohort study.

BACKGROUND: Anemia is common among people living with HIV infection (PLWH) and is associated with adverse health outcomes. Information on risk factors for anemia incidence in the current antiretroviral therapy (ART) era is lacking. METHODS: Within a prospective clinical cohort of adult PLWH receiving care at eight sites across the United States between 1/2010-3/2018, Cox proportional hazards regression analyses were conducted among a) PLWH free of anemia at baseline and b) PLWH free of severe anemia at baseline to determine associations between time-updated patient characteristics and development of anemia (hemoglobin < 10 g/dL), or severe anemia (hemoglobin < 7.5 g/dL). Linear mixed effects models were used to examine relationships between patient characteristics and hemoglobin levels during follow-up. Hemoglobin levels were ascertained using laboratory data from routine clinical care. Potential risk factors included: age, sex, race/ethnicity, body mass index, smoking status, hazardous alcohol use, illicit drug use, hepatitis C virus (HCV) coinfection, estimated glomerular filtration rate (eGFR), CD4 cell count, viral load, ART use and time in care at CNICS site. RESULTS: This retrospective cohort study included 15,126 PLWH. During a median follow-up of 6.6 (interquartile range [IQR] 4.3-7.6) years, 1086 participants developed anemia and 465 participants developed severe anemia. Factors that were associated with incident anemia included: older age, female sex, black race, HCV coinfection, lower CD4 cell counts, VL ≥400 copies/ml and lower eGFR. CONCLUSION: Because anemia is a treatable condition associated with increased morbidity and mortality among PLWH, hemoglobin levels should be monitored routinely, especially among PLWH who have one or more risk factors for anemia.

Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy.

Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.

Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections.

Inflammasomes are multi-protein complexes integrating pathogen-triggered signaling leading to the generation of pro-inflammatory cytokines including interleukin-18 (IL-18). Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections are associated with elevated IL-18, suggesting inflammasome activation. However, there is marked person-to-person variation in the inflammasome response to HCV and HIV. We hypothesized that host genetics may explain this variation. To test this, we analyzed the associations of plasma IL-18 levels and polymorphisms in 10 genes in the inflammasome cascade. About 1538 participants with active HIV and/or HCV infection in three ancestry groups are included. Samples were genotyped using the Illumina Omni 1-quad and Omni 2.5 arrays. Linear regression analyses were performed to test the association of variants with log IL-18 including HCV and HIV infection status, and HIV RNA in each ancestry group and then meta-analyzed. Eleven highly correlated single-nucleotide polymorphisms (r2=0.98-1) in the IL-18-BCO2 region were significantly associated with log IL-18; each T allele of rs80011693 confers a decrease of 0.06 log pg ml-1 of IL-18 after adjusting for covariates (rs80011693; rs111311302 ß=-0.06, P-value=2.7 × 10-4). In conclusion, genetic variation in IL-18 is associated with IL-18 production in response to HIV and HCV infection, and may explain variability in the inflammatory outcomes of chronic viral infections.

Risk of End-Stage Renal Disease in HIV-Positive Potential Live Kidney Donors.

New federal regulations allow HIV-positive individuals to be live kidney donors; however, potential candidacy for donation is poorly understood given the increased risk of end-stage renal disease (ESRD) associated with HIV infection. To better understand this risk, we compared the incidence of ESRD among 41 968 HIV-positive participants of North America AIDS Cohort Collaboration on Research and Design followed for a median of 5 years with the incidence of ESRD among comparable HIV-negative participants of National Health and Nutrition Examination III followed for a median of 14 years. We used risk associations from multivariable Cox proportional hazards regression to derive cumulative incidence estimates for selected HIV-positive scenarios (no history of diabetes, hypertension, AIDS, or hepatitis C virus coinfection) and compared these estimates with those from similarly selected HIV-negative scenarios. For 40-year-old HIV-positive individuals with health characteristics that were similar to those of age-matched kidney donors, viral load <400 copies/mL, and CD4+ count ≥500 cells/µL, the 9-year cumulative incidence of ESRD was higher than that of their HIV-negative peers, yet still low: 2.5 versus 1.1 per 10 000 among white women, 3.0 versus 1.3 per 10 000 among white men, 13.2 versus 3.6 per 10 000 among black women, and 15.8 versus 4.4 per 10 000 among black men. HIV-positive individuals with no comorbidities and well-controlled disease may be considered low-risk kidney donor candidates.

Lessons learned from the design and implementation of myocardial infarction adjudication tailored for HIV clinical cohorts.

We developed, implemented, and evaluated a myocardial infarction (MI) adjudication protocol for cohort research of human immunodeficiency virus. Potential events were identified through the centralized Centers for AIDS Research Network of Integrated Clinical Systems data repository using MI diagnoses and/or cardiac enzyme laboratory results (1995-2012). Sites assembled de-identified packets, including physician notes and results from electrocardiograms, procedures, and laboratory tests. Information pertaining to the specific antiretroviral medications used was redacted for blinded review. Two experts reviewed each packet, and a third review was conducted if discrepancies occurred. Reviewers categorized probable/definite MIs as primary or secondary and identified secondary causes of MIs. The positive predictive value and sensitivity for each identification/ascertainment method were calculated. Of the 1,119 potential events that were adjudicated, 294 (26%) were definite/probable MIs. Almost as many secondary (48%) as primary (52%) MIs occurred, often as the result of sepsis or cocaine use. Of the patients with adjudicated definite/probable MIs, 78% had elevated troponin concentrations (positive predictive value = 57%, 95% confidence interval: 52, 62); however, only 44% had clinical diagnoses of MI (positive predictive value = 45%, 95% confidence interval: 39, 51). We found that central adjudication is crucial and that clinical diagnoses alone are insufficient for ascertainment of MI. Over half of the events ultimately determined to be MIs were not identified by clinical diagnoses. Adjudication protocols used in traditional cardiovascular disease cohorts facilitate cross-cohort comparisons but do not address issues such as identifying secondary MIs that may be common in persons with human immunodeficiency virus.

Recruitment of HIV/AIDS treatment-naïve patients to clinical trials in the highly active antiretroviral therapy era: influence of gender, sexual orientation and race.

BACKGROUND: In the USA, women, racial/ethnic minorities and persons who acquire HIV infection through heterosexual intercourse represent an increasing proportion of HIV-infected persons, and yet are frequently underrepresented in clinical trials. We assessed the demographic predictors of trial participation in antiretroviral-naïve patients. METHODS: Patients were characterized as trial participants if highly active antiretroviral therapy (HAART) was initiated within a clinical trial. Prevalence ratios (PRs) were obtained using binomial regression. RESULTS: Between 1996 and 2006, 30% of 738 treatment-naïve patients initiated HAART in a clinical trial. Trial participation rates for men who have sex with men (MSM), heterosexual men, and women were respectively 36.5, 29.6 and 24.3%. After adjustment for other factors, heterosexual men appeared less likely to participate in trials compared with MSM [PR 0.79, 95% confidence interval (CI) 0.57, 1.11], while women were as likely to participate as MSM (PR 0.97, 95% CI 0.68, 1.39). The participation rate in Black patients (25.9%) was lower compared with non-Black patients (37.5%) (adjusted PR 0.80, 95% CI 0.60, 1.06). CONCLUSIONS: In our clinical setting, gender did not appear to impact participation in HIV treatment trials, but Black patients were slightly less likely to participate in these trials. Considering the substantial proportion of HIV-infected patients who are Black, future trials need to consider strategies to incorporate such underrepresented populations.

Racial and ethnic disparities in COVID-19 disease incidence independent of comorbidities, among people with HIV in the US.

OBJECTIVES: To define the incidence of clinically-detected COVID-19 in people with HIV (PWH) in the US and evaluate how racial and ethnic disparities, comorbidities, and HIV-related factors contribute to risk of COVID-19. DESIGN: Observational study within the CFAR Network of Integrated Clinical Systems cohort in 7 cities during 2020. METHODS: We calculated cumulative incidence rates of COVID-19 diagnosis among PWH in routine care by key characteristics including race/ethnicity, current and lowest CD4 count, and geographic area. We evaluated risk factors for COVID-19 among PWH using relative risk regression models adjusted with disease risk scores. RESULTS: Among 16,056 PWH in care, of whom 44.5% were Black, 12.5% were Hispanic, with a median age of 52 years (IQR 40-59), 18% had a current CD4 count < 350, including 7% < 200; 95.5% were on antiretroviral therapy, and 85.6% were virologically suppressed. Overall in 2020, 649 PWH were diagnosed with COVID-19 for a rate of 4.94 cases per 100 person-years. The cumulative incidence of COVID-19 was 2.4-fold and 1.7-fold higher in Hispanic and Black PWH respectively, than non-Hispanic White PWH. In adjusted analyses, factors associated with COVID-19 included female sex, Hispanic or Black identity, lowest historical CD4 count <350 (proxy for CD4 nadir), current low CD4/CD8 ratio, diabetes, and obesity. CONCLUSIONS: Our results suggest that the presence of structural racial inequities above and beyond medical comorbidities increased the risk of COVID-19 among PWHPWH with immune exhaustion as evidenced by lowest historical CD4 or current low CD4:CD8 ratio had greater risk of COVID-19.

Second-line treatment in the Malawi antiretroviral programme: high early mortality, but good outcomes in survivors, despite extensive drug resistance at baseline.

OBJECTIVES: The Malawi antiretroviral therapy (ART) programme uses the public health approach to identify ART failure. Advanced disease progression may occur before switching to second-line ART. We report outcomes for patients evaluated and initiated on second-line treatment in Malawi. METHODS: Patients meeting Malawi immunological or clinical criteria for ART failure in two large urban ART clinics were evaluated for virological failure (viral load >400 HIV-1 RNA copies/mL) and, if failure was confirmed, initiated on second-line ART (zidovudine/lamivudine/tenofovir/lopinavir/ritonavir). Patients were seen monthly and laboratory evaluations were performed quarterly and as needed. We performed logistic regression modelling to identify factors associated with mortality, mortality or new HIV illnesses, and virological suppression at 12 months. RESULTS: Of the 109 patients with confirmed virological failure, five patients died prior to initiation, three declined switching and 101 patients initiated second-line treatment. Over 12 months, 10 additional patients died, 34 patients experienced 45 HIV-related events, and 19 patients experienced grade 3 or 4 toxicities. Among survivors, 85.2% had HIV-1 RNA<400 copies/mL at 12 months. While power to distinguish differences was limited, response rates were similar regardless of baseline resistance level. The median CD4 count increase was 142 cells/microL. World Health Organization clinical failure at baseline [odds ratio (OR) 3.47; 95% confidence interval (CI) 1.14-10.59] and body mass index <18.5 (OR 4.43; 95% CI 1.15-17.12) were risk factors for death. Baseline CD4 count <50 cells/microL was associated with increased risk for death or morbidity at 12 months (OR 2.57; 95% CI 1.01-6.52). CONCLUSIONS: Second-line treatment in Malawi was associated with substantial mortality, morbidity and toxicity but, among survivors, virological outcomes were favourable.

Ezetimibe alone reduces low-density lipoprotein cholesterol in HIV-infected patients receiving combination antiretroviral therapy.

In this crossover study of ezetimibe monotherapy in 48 antiretroviral-treated patients with human immunodeficiency virus infection, the mean changes in low-density lipoprotein cholesterol were -5.3% (-11 mg/dL) and +5.5% (+4 mg/dL) with ezetimibe treatment and placebo, respectively (P = .04). Ezetimibe was safe and effective in reducing low-density lipoprotein cholesterol and is an option for patients who cannot tolerate treatment with a statin.

The treatment of antiretroviral-naive subjects with the 3TC/zidovudine combination: a review of North American (NUCA 3001) and European (NUCB 3001) trials.

OBJECTIVE: The compound (-)-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine) is a nucleoside analogue with potent in vitro antiretroviral activity, synergy with zidovudine, activity against zidovudine-resistant isolates and minimal cytotoxicity. In early-phase studies, 3TC had a favourable pharmacokinetic profile, was well tolerated by those with HIV infection, and had a modest effect on HIV-1 p24 antigen levels. Although resistance to 3TC monotherapy develops rapidly, the activity of the drug persists. However, zidovudine-resistant virus, in which the 3TC-resistance mutation is selected for, regains phenotypic sensitivity to zidovudine. Therefore, 3TC and zidovudine are a logical combination to evaluate as initial therapy in treatment-naive HIV-1 infected individuals. DESIGN: Two randomized controlled trials, one in Europe and one in North America, evaluated 3TC in combination with zidovudine and compared this combination to zidovudine monotherapy. In the North American study, 3TC monotherapy was also evaluated. In both studies, subjects entered having received less than 4 weeks of zidovudine therapy and no other previous antiretroviral treatments. In the European study, subjects had CD4 cell counts of 100-400/mm3 and received blinded therapy for 24 weeks; they were then offered open-label 3TC and zidovudine for a further 24-week period. In the North American study, initial patient CD4 cell counts were 200-500/mm3, and blinded treatment continued for 52 weeks. Endpoints measured included CD4 cell counts and HIV-1 RNA in plasma, in addition to clinical and laboratory adverse events. RESULTS: In both studies, the combination of 3TC and zidovudine resulted in rises in CD4 counts of 75-85 cells/mm3 that were sustained at 48-60 cells/mm3 above base-line at 48-52 weeks. Effects on HIV-1 RNA levels in plasma also persisted through 48 and 52 weeks at approximately a 90% reduction (1 log10 decrease) from baseline. In the European study, the combination was superior to zidovudine alone over the first 24 weeks, as measured by CD4 and HIV-1 RNA effects, and the addition of 3TC to zidovudine after 24 weeks resulted in a subsequent increase in the mean CD4 count of 39 cells/mm3. In the North American study, the combination of 3TC and zidovudine was better than zidovudine monotherapy when considering the effect on CD4 cells or HIV-1 RNA through 24 weeks. When these treatment groups were compared, using an average of the mean change from baseline of the CD4 counts and HIV-1 RNA levels over that last three study time points (44, 48 and 52 weeks), the combination treatments remained superior to zidovudine alone. In neither study did the addition of 3TC to zidovudine result in additional toxicity. SUMMARY: In two independent studies in patients with limited antiretroviral treatment experience, remarkably similar results were obtained when 3TC/zidovudine in combination was compared to zidovudine monotherapy, demonstrating sustained antiretroviral and immunological effects of the combination over the 48 and 52 weeks of study.

Alternative strategies for anti-HIV treatment.

New HIV treatment strategies are needed. Over the past year, substantial progress has been made in the development of new antiretroviral agents, although the journey from drug discovery to wide clinical use is completed by only a small number of medications. Strategies to enhance immune control and either discontinue or decrease the need for prolonged HAART are under study. The promising preliminary results in very early PHI are in contrast with the minor successes in chronic infection.

Detectable HIV-1 RNA at levels below quantifiable limits by amplicor HIV-1 monitor is associated with virologic relapse on antiretroviral therapy.

OBJECTIVE: To assess the clinical significance of HIV-1 RNA levels detectable using the Amplicor HIV-1 Monitor method but < 400 copies/ml versus levels undetectable by this method. DESIGN: Retrospective cohort study. METHODS: All plasma HIV-1 RNA results over 13 months in our institution were reviewed. The study population comprised all individuals that achieved an HIV-1 RNA level < 400 copies/ml and remained on stable antiretroviral therapy. Results of < 400 copies/ml were stratified as 'below quantifiable limits' (BQL) or 'below detectable limits' (BDL). We examined the incidence of virologic relapse, defined as an HIV-1 RNA level > 400 copies/ml, for individuals with viral loads of BQL or BDL. Cox proportional hazards regression analyses were performed to control for baseline CD4 cell count, the number of antiretroviral medications, and the use of protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTI). RESULTS: Virologic relapse occurred in 52 of 168 individuals over 29,576 person-days overall (incidence rate 1.8 cases/1,000 person-days). The relapse rate was three times greater following HIV-1 RNA levels of BQL rather than BDL [crude rate ratio 3.2; 95% confidence interval (CI) 1.8-5.8]. After adjusting for baseline CD4 cell count, number of antiretroviral medications, and use of PI and/or NNRTI, the rate of relapse was nearly four times greater for individuals with HIV-1 RNA levels of BQL (hazard ratio 3.7; 95% CI 2.0-6.7). CONCLUSIONS: In a large clinic population, low-level HIV-1 RNA detected in plasma below the 400 copies/ml limit of quantifiability for Amplicor HIV-1 Monitor was associated with an increased rate of virologic relapse on therapy.

Detection and biologic characterization of infectious HIV-1 in semen of seropositive men.

OBJECTIVE: Factors that influence the infectivity of an individual and the impact of antiviral treatment on infectivity are not well defined. This study investigated the value of a sensitive method for detecting infectious HIV in semen for use as a marker for infectivity. DESIGN: A cross-sectional study of infectious HIV in the semen of 33 HIV-positive men. METHODS: A sensitive method for detecting infectious HIV in semen was used. The correlation of culture in semen with clinical and laboratory data was investigated. Biological phenotypes of isolates from blood and semen were tested using an MT-2 assay. RESULTS: HIV cultures from seminal cells were positive in 18 patients (55%) and in one patient from seminal plasma. Higher recovery rates of HIV from semen correlated with a low CD4 count (80% in patients with a CD4 count > 100 x 10(6)/l versus 33% in patients with a CD4 count < 100 x 10(6) cells; P < 0.025) and symptomatic disease (78 versus 27% in asymptomatic patients; P < 0.01). Recovery of HIV from semen was independent of presence or absence of plasma viremia and the biological phenotype of blood isolates. Ten patients with syncytium-inducing (SI) isolates in their blood had positive semen cultures for HIV. Seven of the 10 patients had SI isolates recovered from their semen, whereas three had non-SI isolates only. CONCLUSION: Data from partner studies show higher rates of HIV transmission for patients with low CD4 counts and symptomatic disease. The compatibility of epidemiologic data with our finding that significantly more HIV is recovered in semen from patients with advanced disease, suggests that HIV culture of semen samples may provide a useful surrogate marker to measure infectivity in clinical studies. Further studies are needed to define the inoculum required to transmit HIV and to study the impact of sexually transmitted diseases and HIV-1 phenotype on semen infectivity.

Quantification of HIV in semen: correlation with antiviral treatment and immune status.

OBJECTIVE: This study examined the concentration of HIV in semen and the effects of biological factors on HIV excretion. METHODS: Semen samples from 101 men at different stages of the disease were evaluated by quantitative HIV culture and HIV RNA detection. Blood plasma samples were available from 56 patients. The effects of CD4 and CD8 count, blood plasma RNA levels, treatment status and clinical staging on the shedding of HIV were evaluated. RESULTS: HIV RNA levels in semen correlated with quantitative HIV culture of seminal cells and a strong association of positive seminal cell culture with high RNA levels was observed. CD4 count and antiviral treatment were inversely correlated with the concentration of HIV in semen. Blood plasma HIV RNA values were correlated with HIV RNA levels in semen, although some patients had highly discrepant results. CONCLUSIONS: The strong correlation between seminal cell culture and concentration of HIV RNA in seminal plasma suggested that HIV detected in seminal plasma was released by productively infected cells in the male genital tract. The study showed that the concentration of HIV in semen, which was likely to be correlated with HIV infectivity, was a function of the immune status of the HIV-infected individual. The results suggested that antiviral therapy may have reduced the concentration of HIV in semen.

HIV-1 RNA levels and the development of clinical disease. North American Lamivudine HIV Working Group.

OBJECTIVE: To assess the prognostic value of HIV RNA levels for predicting clinical disease independently of the CD4 lymphocyte count in patients on antiretroviral therapy. DESIGN: Cohort of HIV-infected patients from two trials of lamivudine therapy. PATIENTS: For 620 patients randomized in the North American NUCA3001 and NUCA3002 trials of lamivudine, HIV RNA levels were measured (median, seven measures per patient) and CD4 counts were assessed at a central laboratory (median, 13 counts per patient). Patients were in the 1993 Centers for Disease Control and Prevention (CDC) stages A (n = 439), B (n = 135) or C (n = 46) at baseline. OUTCOME MEASURES: For patients who were in CDC stage A at baseline we considered the ability of HIV RNA levels and CD4 counts to predict the development of CDC stage B or C disease. A Cox proportional hazards model was used. In a second analysis, patients who were AIDS-free at baseline were considered, and the endpoint was AIDS (CDC stage C). RESULTS: Patients' initial CD4 counts ranged (5-95% centiles) from 104 to 529 x 10(6)/l (median, 274 x 10(6)/l) and HIV RNA levels from 1900 to 339680 copies/ml (median, 44240 copies/ml). For the first analysis, with CDC stage B or C disease as endpoint, both the most recent HIV RNA level and CD4 count predicted the development of clinical disease [relative hazard (RH) for HIV RNA, 1.96 per 10-fold difference in HIV RNA; 95% confidence interval (CI), 1.41-2.73; P = 0.0001; and RH for CD4 count, 1.82 per twofold difference in CD4 count; 95% CI, 1.27-2.56; P = 0.0009]. When both HIV RNA and CD4 count were included in a multiple regression model, both markers provided information additional to that given by the other (RH for HIV RNA, 1.75; 95% CI, 1.23-2.50; P = 0.002; and RH for CD4 count, 1.40; 95% CI, 0.95-2.07; P = 0.09). In the second analysis, with AIDS as endpoint, both HIV RNA level (P = 0.02) and CD4 count (P = 0.004) were independently associated with clinical progression. These results were essentially unchanged after adjustment for treatment arm (zidovudine/lamivudine versus control arms). CONCLUSION: The HIV RNA level shows ability to predict the development of clinical disease and may thus be of importance in addition to the CD4 count in patient monitoring.

Drug resistance and virologic response in NUCA 3001, a randomized trial of lamivudine (3TC) versus zidovudine (ZDV) versus ZDV plus 3TC in previously untreated patients.

OBJECTIVE: To study the effect of HIV-1 resistance to lamivudine (3TC) and zidovudine (ZDV), and syncytium-inducing (SI) phenotype on virologic response to treatment with ZDV, 3TC, or ZDV plus 3TC in previously untreated individuals with HIV-1 infection. DESIGN: A prospective virologic substudy of GlaxoWellcome protocol NUCA 3001. METHODS: HIV-1 isolates obtained at study entry and at week 12 were expanded in peripheral blood mononuclear cell (PBMC) culture, titered, and assayed for phenotypic and genotypic evidence of resistance to ZDV and 3TC, and for syncytium formation on MT-2 cells. RESULTS: Phenotypic and genotypic resistance to 3TC was detected in the majority of HIV-1 isolates from patients who received 3TC alone or in combination with ZDV. Despite showing 3TC resistance, subjects who received 3TC in combination with ZDV had significantly greater decreases in plasma HIV-1 RNA levels compared with those who received ZDV alone. Occurrence of the K7OR ZDV resistance mutation was significantly reduced in patients who received the 3TC/ZDV combination as compared with patients on ZDV monotherapy. Plasma HIV-1 RNA returned to near-baseline levels more quickly in patients with SI isolates at study entry. CONCLUSIONS: Despite the rapid emergence of 3TC resistance, combination therapy with 3TC plus ZDV resulted in greater reduction in plasma HIV-1 RNA levels over 24 weeks as compared to ZDV monotherapy. Prevention of ZDV resistance may contribute to the sustained activity of the combination therapy.

Correspondence between the effect of zidovudine plus lamivudine on plasma HIV level/CD4 lymphocyte count and the incidence of clinical disease in infected individuals. North American Lamivudine HIV Working Group.

OBJECTIVES: To investigate whether apparently beneficial changes in plasma HIV RNA level and CD4 lymphocyte count that are induced by antiretroviral therapy are associated with a corresponding clinical benefit. METHODS: For 620 patients in two randomized, double-blind trials of lamivudine (3TC) and zidovudine (ZDV) plasma HIV RNA and CD4 lymphocyte count changes were compared in patients randomized to 3TC plus ZDV and patients randomized to other treatment arms. The effect of therapy on the HIV RNA level and CD4 count was compared with the effect of therapy on clinical endpoints over the same time period. RESULTS: Median baseline values for all subjects were 42 420 copies/ml for HIV RNA and 277 x 10(6)/l for CD4 count. During the trial a significantly lower HIV RNA level and higher CD4 count was sustained in the ZDV/3TC group compared with the other group, with a difference in the median area under the curve from baseline per month of follow-up of 0.38 log10 copies/ml HIV RNA and 0.18 log2 x 10(6)/l CD4 cells (P < 0.001 in each case). For patients who were initially asymptomatic or in CDC stage B, the adjusted relative hazard (RH) of AIDS for a twofold lower CD4 count was 3.14 [95% confidence interval (CI), 1.44-6.83] and for a 10-fold higher HIV RNA level was 3.22 (1.20-8.59). The RH progression to AIDS expected with ZDV/3TC compared with the control treatments, given the observed effects of treatment on CD4 cell counts and HIV RNA levels, is 0.52, whereas the observed value was 0.16 (0.03-0.74). After adjustment for HIV RNA and CD4 changes over time the observed RH of progression to AIDS for ZDV/3TC treatment compared with controls was increased to 0.36 and was no longer significant (95% CI, 0.07-1.85). CONCLUSION: In this analysis of two trials, the effects of ZDV/3TC in reducing plasma HIV RNA and raising peripheral blood CD4 counts were associated with concurrent clinical benefits and the effect of treatment on these markers could account for at least part of the clinical benefits of therapy that were observed.

Efficacy, safety, and adherence with a twice-daily combination lamivudine/zidovudine tablet formulation, plus a protease inhibitor, in HIV infection.

OBJECTIVE: A randomized, open-label, multicenter study to establish clinical equivalence (non-inferiority) of a regimen employing a lamivudine 150 mg/zidovudine 300 mg combination tablet, administered twice daily, plus a marketed protease inhibitor, compared with a conventional regimen of 150 mg lamivudine twice daily, 600 mg zidovudine daily, and a protease inhibitor, in antiretroviral-experienced patients infected with HIV-1. PATIENTS: Adults who were seropositive for HIV-1 infection with plasma HIV-1 RNA levels < 10000 copies/ml (Roche Amplicor polymerase chain reaction assay, lower limit of quantitation (LLOQ) 400 copies/ml) and CD4+ cell counts > or = 300 x 10(6)/l). All patients had been receiving the conventional lamivudine/zidovudine/protease inhibitor regimen for > or = 10 weeks immediately prior to the study. INTERVENTION: Patients were randomized to the conventional regimen (n = 113) or combination tablet regimen (n = 110) for 16 weeks. The primary study endpoint was treatment failure, defined as an increase in HIV-1 RNA > or = 0.5 log10 above baseline in patients with viral load > LLOQ at randomization and as HIV-1 RNA increasing to > or = 1250 copies/ml in patients with viral load < LLOQ at randomization. RESULTS: The combination tablet regimen was associated with a 3.5% greater success rate than the conventional regimen (96.4 versus 92.9%), with four and eight patients failing treatment due to increases in HIV-1 RNA levels, respectively. The lower limit of the associated confidence interval for the difference was -2.4%, which was well within the -10% margin predefined as clinically unimportant. This establishes the clinical equivalence (non-inferiority) of the combination tablet regimen to the conventional regimens regarding virologic response. The combination tablet and conventional regimens were similar with respect to percentage of patients maintaining HIV-1 RNA levels < LLOQ at the end of study or improving from baseline to undetectability (94 versus 91%; P= 0.063), overall incidence of drug-related adverse events (21 versus 19%) (P=0.868), and mean area under the curve for CD4+ cell counts [treatment difference, 5.9 cells (95% confidence interval, -15.8 to 27.6 x 10(6) cells/l)]. A self-reported adherence questionnaire indicated that patients in the combination tablet group were less likely to miss doses of nucleoside analogue medication at weeks 8 (P= 0.007) and 16 (P= 0.046). CONCLUSIONS: The combination lamivudine/zidovudine tablet/protease inhibitor regimen is clinically equivalent (non-inferior) to the conventional regimen with respect to virologic response and may offer adherence advantages.