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PubMed2005

HIV-1 drug resistance evolution among patients on potent combination antiretroviral therapy with detectable viremia.

Many patients infected with HIV do not achieve or maintain virologic suppression below levels of detection while on potent combination antiretroviral therapy. The likelihood of emergence of incident mutations conferring reduced antiretroviral drug susceptibility was estimated among patients maintained on a stable regimen with ongoing detectable plasma HIV RNA levels. Ninety-eight HIV-infected patients were identified who had 2 genotypic antiretroviral resistance tests available. Poisson log-linear regression models were used to identify predictors and estimate incidence rates of number of acquired antiretroviral drug resistance mutations per person-year. At the 1st resistance test, 88% of patients had evidence of at least 1 mutation. Sixty percent of patients acquired at least 1 new mutation during a median of 9.3 months between consecutive resistance tests, with an incidence rate of 1.61 acquired mutations per person-year (95% CI: 1.36-1.90). Predictors of resistance evolution included average plasma HIV RNA level, HIV RNA slope, and number of mutations detected at the 1st resistance test. The likelihood of acquiring drug resistance mutations while remaining on potent combination antiretroviral therapy that does not confer complete suppression of HIV replication is relatively low and depends on the level of viral replication and prior resistance.

Adult↗
PubMed2006

Persistence of a sexually transmitted highly resistant HIV-1: pol quasispecies evolution over 33 months in the absence of treatment.

The evolution of a sexually transmitted multiresistant HIV-1 in a linked transmission chain was followed for 33 months to assess its potential to persist in the absence of treatment. The multiresistant HIV reverted slowly to wild type in reverse transcriptase (positions 44, 67, 74, 118) rendering the virus only susceptible to lamivudine/emtricitabine. Persistence of the replication-competent resistant HIV increases its potential to spread further and strengthens the importance of resistance testing in newly infected patients.

Adult↗
PubMed2006

Rapid reversion of sequence polymorphisms dominates early human immunodeficiency virus type 1 evolution.

The error-prone replication of human immunodeficiency virus type 1 (HIV-1) enables it to continuously evade host CD8+ T-cell responses. The observed transmission, and potential accumulation, of CD8+ T-cell escape mutations in the population may suggest a gradual adaptation of HIV-1 to immune pressures. Recent reports, however, have highlighted the propensity of some escape mutations to revert upon transmission to a new host in order to restore efficient replication capacity. To more specifically address the role of reversions in early HIV-1 evolution, we examined sequence polymorphisms arising across the HIV-1 genome in seven subjects followed longitudinally 1 year from primary infection. As expected, numerous nonsynonymous mutations were associated with described CD8+ T-cell epitopes, supporting a prominent role for cellular immune responses in driving early HIV-1 evolution. Strikingly, however, a substantial proportion of substitutions (42%) reverted toward the clade B consensus sequence, with nearly one-quarter of them located within defined CD8 epitopes not restricted by the contemporary host's HLA. More importantly, these reversions arose significantly faster than forward mutations, with the most rapidly reverting mutations preferentially arising within structurally conserved residues. These data suggest that many transmitted mutations likely incur a fitness cost that is recovered through retrieval of an optimal, or ancestral, form of the virus. The propensity of mutations to revert may limit the accumulation of immune pressure-driven mutations in the population, thus preserving critical CD8+ T-cell epitopes as vaccine targets, and argue against an unremitting adaptation of HIV-1 to host immune pressures.

CD8-Positive T-Lymphocytes↗
PubMed1997

Host-specific driving force in human immunodeficiency virus type 1 evolution in vivo.

To investigate the process of human immunodeficiency virus type 1 (HIV-1) evolution in vivo, a total of 179 HIV-1 V3 sequences derived from cell-free plasma were determined from serial samples in three epidemiologically linked individuals (one infected blood donor and two transfusion recipients) over a maximum period of 8 years. A systematic analysis of pairwise comparisons of intrapatient sequences, both within and between each sample time point, revealed a preponderance and accumulation of nonsynonymous rather than synonymous substitutions in the V3 loop and flanking regions as they diverged over time. This strongly argues for the dominant role that positive selection for amino acid change plays in governing the pattern and process of HIV-1 env V3 evolution in vivo and nullifies hypotheses of purely neutral or mutation-driven evolution or completely chance events. In addition, different rates of evolution of HIV-1 were observed in these three different individuals infected with the same viral strain, suggesting that the degree of positive pressure for HIV-1 amino acid change is host dependent. Finally, the observed similar rate of accumulation in divergence within and between infected individuals suggests that the process of genetic divergence in the HIV epidemic proceeds regardless of host-to-host transmission events, i.e., that transmission does not reset the evolutionary clock.

Amino Acid Sequence↗
PubMed1998

A longitudinal study of seroreactivity against Mycoplasma penetrans in HIV-infected homosexual men: association with disease progression.

We investigated the relationships between a putative cofactor of HIV infection, Mycoplasma penetrans, and the evolution of HIV disease. The evolution of titers of anti-M. penetrans antibodies in 58 randomly selected HIV-seropositive adult homosexual men was investigated. The median length of follow-up was 38 months. Thirty-six individuals was investigated. The median length of follow-up was 38 months. Thirty-six individuals (62.1%) remained M. penetrans seronegative (group 0). Fourteen patients (24.1%) had consistently low antibody titers or low antibody titer(s) in at least one sample and negative test(s) in the other(s). This pattern was possibly associated with latent or earlier infection (group 1). Eight patients (13.8%) had moderate to high antibody titers for long periods, indicating an active and persistent M. penetrans infection (group 2); four patients in this group presented a serological reactivation and thus probably developed an acute infection during the study; two had a stable and moderate level of antibody throughout the study; in two patients the antibody titers decreased substantially. Interestingly, CD4 cell counts declined more rapidly in group 2 than in group 0 (medians of -4.5 versus -2.1 cells/mm3/month, p < 0.05 and -0.16 versus 0 cell percentage/month, p < 0.05), whereas there was no significant difference between groups 1 and 0 (medians of -2.0 versus -2.1 cells/mm3/month and -0.15 versus 0 cell percentage/month). In patients with serological reactivation, the viral load was higher in sera with higher M. penetrans antibody titers. These findings suggest an association between active M. penetrans infection and progression of HIV disease.

AIDS-Related Opportunistic Infections↗
PubMed1999

A combinatorial ledge: reverse transcriptase fidelity, total body viral burden, and the implications of multiple-drug HIV therapy for the evolution of antiviral resistance.

The chronicity, high mutation rates, and high circulating titers of HIV during the 'stable' phase of infection make rapid evolution of resistance mutations a key predictor of antiretroviral efficacy. Recent advances in measurement of viral RNA titers, turnover dynamics and the in vivo spectrum of resistance mutations allow realistic in vivo estimates of important kinetic parameters of within-patient evolution of viral resistance. First-order estimates of the frequency of viral genotypes necessary for resistance to many antiretroviral combination regimens indicate that many such genotypes pre-exist in patients prior to initiation of therapy. The combinatorial nature of observed multiply-resistant genotypes, however, along with current estimates of total-body viral load and viral turnover dynamics, imply a strikingly sharp transition associated with the change from two-drug to three-drug antiretroviral regimens: pre-existing resistance being near-certain in the first instance but highly unlikely in the second. This abrupt change, a 'combinatorial ledge', carries with it a number of important implications for the understanding and control of HIV infection and other potential targets of antiviral therapy.

Anti-HIV Agents↗
PubMed2005

[Treatment interruption in HIV infected patients: clinical and biological evolution].

OBJECTIVE: The authors had for aim to evaluate the clinical and biological evolution in HIV-infected patients with viraemia lower than 30,000 copies/mL having decided to interrupt their treatment. PATIENTS AND METHODS: Patients with highly active antiretroviral therapy (HAART) for more than 3 months followed by treatment interruption longer than 1 month were included in a retrospective analysis. RESULTS: Forty-six patients having stopped treatment between November 1999 and July 2003 were included. The median duration of treatment interruption was 9.5 months. During the study, no clinical event occurred for 21 patients, and at least 1 clinical event occurred for the 25 others. The median CD4(+) cell counts (CD4) before and at the end of treatment interruption were 597/mm(3) and 437/mm(3), respectively (P<0.001). The median values of viral load before and at the end of treatment interruption were <50 and 23749 copies/mL, respectively (P<0.001). Among the 26 patients having started a new HAART, pre-treatment interruption and post-new HAART median CD4 (with a median delay after HAART of 9.7 months) were 548 and 432.5/mm(3) (P=0.02). Pre-treatment interruption and post-new HAART median viral load were 131.5 and 94.5 copies/mL (NS). CONCLUSIONS: Treatment interruption must be used with caution in spite of the absence of virological impact, because CD4 cell count after new HAART is lower than CD4 preceding treatment interruption. Treatment interruption is contraindicated for patients with AIDS. Physicians must carefully follow other patients who decide on a treatment interruption.

Adult↗
PubMedDate not supplied

[Natural history of HIV infection in the child].

The evolution of HIV infection acquired by vertical transmission is more rapid in children than in adults. Mean survival ranges from 75 to 90 months and only 70% of children reach the age of 6. The natural history has two different patterns. Approximately 15-20% of the children develop severe immunodeficiency with opportunist infections and encephalopathy in the first year of life and die within the first three years. In the remaining 80-85%, the progression of the disease is slower and they live for several years. It has been postulated that the first group is constituted by cases of intrauterine transmission, whereas transmission is closer to birth in the second group. Aside from the moment of transmission, other factors--maternal, infant, and viral--influence the evolution of the disease. There is a direct relation between the severity of maternal disease and the risk that the child will acquire opportunist infections or die in the early years of life. The evolution of the disease also depends on clinical manifestations. The development of opportunist infections, encephalopathy, and delayed height and weight gain are associated with rapid progression, whereas lymphoid interstitial pneumonia and parotitis are associated with a slower progression. Viral load probably is the factor that best predicts the course of infection, although the load values associated with slow or rapid progression have not been clearly defined. However, it is evident that the lower the viral load, the lower the risk of infection. Although the viral load may be undetectable at birth, it rapidly reaches very high values, higher than in adults. Moreover, the state of equilibrium may take several years to attain. In any case, a linear relation cannot be established between viral load and the risk of progression, so other markers must be evaluated, such as CD4.

AIDS Dementia Complex↗
PubMed2000

[Evolution of the prevalence of HIV infection and risk behavior of drug injection among intravenous drug users infected or not infected by HIV in 3 Spanish cities. Working Group of Physicians of the World for the monitoring of HIV infection and risk behaviors in intravenous drug users].

OBJECTIVE: To know the evolution of HIV prevalence and risk behavior practices of drug injection in three spanish cities on the basis of the serologic status of injecting drug users. METHODS: Cross-sectional surveys among users in syringe interchange programmes. RESULTS: HIV prevalence (self-reported) decreased in Madrid from 50% (1992) down to 41% (1996) (p = 0.01) and did not change in Seville and Valencia from 1994 to 1996. Among HIV-positive injecting drug users, a decrease was observed in the practice of giving and taking used syringes in the three cities, although this decrease reached a statistically significance (p = 0.006) only for giving in Valencia from 1994 to 1996 and was almost significant (p = 0.08) for taking in Madrid from 1993 to 1996. Among HIV-negative injecting drug users, no decreases were observed in the practice of giving and taking used syringes and even a significant increase in giving syringes in Seville was recorded (p = 0.01) from 1994 to 1996. CONCLUSIONS: HIV prevalence among injecting drug users is stabilized or decreasing in the three studied cities. The prevalence of injecting risk behavior evolves differently according to the serologic status.

Adult↗
PubMed2006

The contribution of HIV fitness to the evolution pattern of reverse transcriptase inhibitor resistance.

All currently recommended anti-retroviral therapy protocols employ reverse transcriptase inhibitors (RTIs). However, mutations within the reverse transcriptase (RT) domain can lead to resistance to these agents and treatment failure. The contribution of the fitness of drug-resistant species to the evolution of RTI resistance has not been elucidated despite its potential implications for therapeutic strategies. In this study we utilized a competitive fitness assay to assess the relative fitness of 13 drug-resistant HIV-1 mutants in the presence and absence of inhibitor. Among these mutants were thymidine analog mutations (TAMs) such as 41L/210W/215Y and 67N/70R/219Q, as well as single mutants such as 103N and 181C that confer high-level resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine. These studies revealed that 67N/70R and 67N/70R/219Q were fitter than the 70R progenitor species, and the acquisition of 41L by 215Y substantially increased its fitness in the absence of drug. We also observed that 215Y was more fit than 70R and 67N/70R, and that 41L/215Y and 41L/210W/215Y were the most-fit species in the presence of zidovudine. Moreover, 103N was fitter than 181C without nevirapine but less fit with nevirapine. From these studies we conclude that viral fitness contributes substantially to the evolutionary pattern of TAMs suggesting that, as for protease inhibitor resistance, mutations can act in primary (increasing resistance) and secondary (increasing fitness) capacities. We also surmise that drug resistance and fitness are competing forces underlying the emergence of nevirapine resistant mutants 103N and 181C.

Anti-HIV Agents↗
PubMed2005

HIV type 1 fitness evolution in antiretroviral-experienced patients with sustained CD4+ T cell counts but persistent virologic failure.

BACKGROUND: Over recent years, treatment guidelines for human immunodeficiency virus (HIV) infection have evolved from monotherapy to combination regimens that include > or = 3 active drugs, resulting in a sharp decrease in morbidity and mortality. In the present article, we evaluated changes in HIV type 1 viral fitness associated with the sequential introduction of antiretroviral treatment strategies in 4 chronically infected patients with sustained CD4 cell count despite having a persistently detectable viral load. METHODS: Plasma samples were obtained before and during treatment to construct recombinant virus containing the 3'-end of gag, the protease and the reverse-transcriptase coding region. Drug susceptibility phenotype was evaluated with a panel of multiple reverse-transcriptase and protease inhibitors. Replicative capacity (RC) and infectivity were measured, and production of p24 was monitored after transfection. RESULTS: Multidrug-resistant (MDR) viruses selected during long-term antiretroviral therapy were less fit and infectious than their wild-type or monotherapy-selected counterparts, with the exception of viruses recovered from patient B. In 3 of 4 cases, p24 kinetics after transfection showed a delay in viral production of recombinant viruses containing MDR mutations. Data from the RC and infectivity assays showed good correlation (P < .03) and corroborated the p24 kinetics data. CONCLUSIONS: This study shows that accumulation of MDR mutations during long-term antiretroviral treatment results, albeit not in all cases, in reductions of viral fitness.

Anti-HIV Agents↗
PubMed2002

HIV mutagenesis and the evolution of antiretroviral drug resistance.

The development of antiretroviral drug resistance is a major threat to the effective treatment of human immunodeficiency virus type 1 (HIV-1) infection. Drug treatment failure is associated with accumulation of drug resistance mutations and the evolution of drug resistance. Studies from microbial systems provide evidence for a correlation between drug resistance development and increased pathogen mutation rates. Recent studies with HIV-1 have shown that drugs targeted against reverse transcriptase (RT) as well as drug-resistant RT can increase HIV-1 mutation frequencies. Furthermore, combinations of drug and drug-resistant RT have been found to increase virus mutation frequencies in a multiplicative manner. The correlation of increased HIV-1 mutation rates with the evolution of antiretroviral drug resistance indicates that drug failure could increase the likelihood of further resistance evolving from subsequent drug regimens.

Anti-HIV Agents↗
PubMed2003

Factors associated with the evolution of the viral load in individuals with HIV infection.

The temporal evolution of the viral load (VL) in a group of patients under clinical care and the identification of individual variables that determined this evolution was studied using a retrospective descriptive study of the VL determinations on 1336 patients between September 1996 and June 2000. During follow-up, patients' VLs increasingly fell below the detection threshold. Those patients who had received antiretroviral treatment prior to the monitoring of the viraemia presented lower VLs at the start of their follow-up. Those patients who had been cared for on the same unit throughout their follow-up maintained lower VLs. Female patients uniformly presented lower VL results than the males. The immunological status at the beginning of follow-up and the basal VL determined the initial evolution of the patients' VL, although it did not do so in the final stages of follow-up. The immunological and virological state at the onset of the follow-up determines the evolution of the patients' VL.

Adolescent↗
PubMed1991

[Immunologic profile of HIV-2 seropositive African individuals (follow-up)].

In the geographic distribution of HIV-2, it is known that this infection is most prevalent in West Africa. Since 1986 we have studied seropositive and seronegative clusters, in Guinea-Bissau with follow-ups in 1988, 1989, 1990 and 1991. Analysis of the results show the high incidence of this infection. 8.51% of the 4,372 people of the general population studied were seropositive, showing the high predominance of HIV-2 infection. Only 4 cases were exclusively reactive to HIV-1 and a slow evolution of HIV-1 infections. In the seroconversions of HIV-2 infections the antibodies appeared first to the core components and secondly to the surface glycoproteins. Some of the laboratory parameters affected in the evolution of the infection include a gradual increase in immunoglobulins and a decrease in CD4 lymphocytes and in the CD4/CD8 ratio. A comparison of these variations in HIV-2 infected people, with or without cross-reactivity to HIV-1, reveals that they are much more evident in exclusively HIV-2 positive people. This fact can indicate that the variants responsible for the cross-reactions are less pathogenic and phylogenetically less developed.

Africa, Western↗
PubMed2006

Impact of HIV-1 pol diversity on drug resistance and its clinical implications.

PURPOSE OF REVIEW: HIV knowledge is based on subtype B, common in resource-rich settings, whereas globally non-B subtypes predominate. Inter-subtype pol diversity encompasses multiple genotypic differences among HIV variants, the consequence of which is unknown. This review summarizes publications from the past year relevant to the impact of HIV diversity on drug resistance evolution and its potential clinical implications. RECENT FINDINGS: The benefit of antiretroviral therapy in non-B infected patients is ongoing, though subtype heterogeneity in rates of disease progression is observed. Pol inter-subtype diversity is high, and known subtype B drug resistance mutations occur in non-B subtypes. New mutations and subtype-specific mutation rates are identified, however, unexplained drug susceptibilities are seen, and additional insight is offered on structural pathogenic mechanisms of resistance in non-B subtypes. These differences may affect genotypic interpretation and our ability to apply drug resistance to patient care. SUMMARY: Current evidence suggests good treatment response and comparable drug resistance evolution in HIV-1 B and non-B infected patients, with increasingly emerging differences. Impact of inter-subtype diversity on drug susceptibility and on evolution of drug resistance should continue to be a major research focus to increase our understanding and ability to improve global patient care.

Algorithms↗
PubMed2007

Virological characterization of an infection with a dual-tropic, multidrug-resistant HIV-1 and further evolution on antiretroviral therapy.

We studied a case of recent infection with multidrug-resistant (MDR) HIV-1. Over 16 months off-therapy, the CD4 cell count decreased from 419 to 184 cells/mul. Antiretroviral therapy (ART) then led to an incomplete virological response but to an immunological benefit, concurrently with a shift to CCR5-only tropism and a reduction in replication capacity. ART, even if suboptimal, can be of interest in the case of MDR virus infection.

Adult↗
PubMed2007

The evolution of the CDC HIV prevention capacity-building assistance initiative.

As the HIV/AIDS epidemic neared the end of its first decade in the late 1980s, the US Centers for Disease Control and Prevention (CDC) recognized the disparate impact on racial and ethnic minority communities. In response, a program was initiated to build capacity to prevent the further spread of HIV and other STDs in these communities. Since that time, the program has expanded in scope, intensity of efforts, and funding. Today, the CDC's Capacity Building Assistance (CBA) Initiative serves communities across the nation by building community, organizational, and HIV prevention program/intervention capacity designed to reduce the number of new HIV infections among at-risk populations. This article focuses on the history and evolution of these efforts, lessons learned, and how these were used to develop the current, more responsive system. A conceptual framework is presented that describes the taxonomy of CBA services designed to (1) enhance organizational infrastructure; (2) enhance HIV prevention interventions; (3) strengthen community capacity; and (4) strengthen community planning. It includes language and definitions, approaches and mechanisms for delivering capacity-building services, and a Web-based request-and-referral system that serves as the foundation for tracking, monitoring, and ensuring the delivery of appropriate, efficient, and culturally competent CBA.

Centers for Disease Control and Prevention, U.S.↗